Current findings from clinical trials and observational studies on the association between HT use and the risk of cognitive decline, dementia, and AD have investigated previously putative lifestyle, socioeconomic, and genetic factors affecting this association. The type of HT, its dose, duration, and formulation along with time of initiation with respect to the onset of natural menopause or induced menopause, and health status at baseline are among those factors which influence the onset of dementia, cognitive decline, and AD.
Recent clinical trials such as KEEPS and ELITE (Early versus Late Intervention Trial with Estradiol) have provided additional information about HT use and cognitive decline. ELITE explored the risk of cognitive decline in the context of the serum hormone levels among women within 6 and 10 years of their menopause. The endogenous estrogen level was not associated with verbal memory in either group, while sex hormone binding globulin and progesterone were positively associated with verbal memory in the early group only (Henderson et al., 2013). Moreover, in a recent study from the ELITE trial, the use of estradiol when initiated within 6 years of menopause did not affect cognitive status differently than initiation of >10 years after menopause. HT use was neither beneficial nor harmful to cognition at these two time points (Henderson et al., 2016). Similarly findings from the KEEP-cog trial concluded that menopausal hormone therapy was neither beneficial nor harmful for cognition, while low dose oral-CEE but not transdermal estradiol, improved symptoms of anxiety and depression (Gleason et al., 2015). Therefore, these findings do not support the concept of use of HT within a certain time window that is around menopause as was suggested from the results originating from WHIMS. However, findings from KEEPS-cog are not generalizable to women using HT for >4 years and, but importantly, in neither trial (KEEPS-cog and ELITE), was menopausal hormone therapy found to be harmful in young women.
A recent development in the use of HT has been based on research supporting the critical time period, low dose estrogen is recommended to alleviate menopausal symptoms but only for a short duration of time (Scott et al., 2014). Moreover, according to a recent Cochrane reviews, fractures are the only outcome for which there is strong evidence of benefits from HT use, whereas there are little or no benefits of HT on cardiovascular diseases, and there may be a higher risk of adverse events such as stroke, dementia, and venous thromboembolic events (Marjoribanks et al., 2012, Boardman et al., 2015). However, the current consensus statement on menopausal hormone therapy recommends initiation of HT before age 60 or within 10 years after menopause, but does not provide any guidelines on its discontinuation (de Villiers et al., 2016).
Considering the systemic complications of oral HT use despite its neuroprotective potential, the focus has been to develop SERM drugs which would have tissue specific effects, for example, the drug would have neuroprotective effects through binding to estrogen receptors in brain only, while sparing peripherally located estrogen receptors in uterus and breast etc. to avoid HT-related peripheral deleterious effects (Barron, Pike 2012). The currently available SERMs act as estrogen antagonists in brain and thus do not exert the neuroprotective effects of estrogen (Komm and Mirkin 2003). A new approach in this context is the tissue selective estrogen complex (TSEC). TSEC refers to a combination of SERM with one or more estrogens, which aims to combine the agonistic activity of estrogens on estrogen receptors along with the tissue selectivity of SERMs (Komm and Mirkin 2013).
Both TSEC and SERM can be used without progesterone even in women with an intact uterus, which is a promising approach as it can avoid progesterone related side effects (Santen et al. 2014). Molecular and pharmacological effects of estrogens, SERMs and TSEC differ from each other. Recently TSEC has been claimed to be a promising therapy where the neuroprotective effect of estrogen is combined with SERMs to prevent the peripheral harmful effects of estrogens (Komm and Mirkin 2013).
Another recent concept in the HT and dementia relationship is to compare the effect of short-term HT use (2-3 years) among recently menopausal women which is then stopped versus those who use HT for a longer duration. In one study, this former approach was associated with a 66% relative reduction in the risk of cognitive decline independent of age, alcohol use, smoking, and education. This finding suggests that there might be long term beneficial effects linked with the short term HT use around menopause (Bagger et al., 2005).
The reasons for the inconsistent findings from clinical trials and observational studies need to be clarified; why on one side do observational studies usually favor the use of HT to protect against dementia and cognitive decline, but these positive results cannot be duplicated in clinical trials?
Based on results from this thesis and the literature review, it is tempting to consider estrogen as a neuroprotective hormone, yet its clinical impact seems to be double-edged – in some cases it is beneficial – in others, it is detrimental. Considering recent advances and the exploration of the critical time period for HT use theory in the KEEPS-cog and ELITE trials, the next step might be to re-examine the population from KEEPS-cog once the participants reach the age of onset of dementia. Since the KEEPS-cog trial examined the association of 4 years of HT use around menopause with cognition, it could be an excellent source to examine the long-term effects of short-term HT use around menopause on cognitive decline and dementia, as suggested by one previous study [Bagger et al., 2005]. Similarly, clinical trials with tissue (especially brain) specific estrogen receptor modulators might add more pieces to the AD-HT jigsaw puzzle.
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